The goal of Project 4 is to understand the crosstalk between innate immune sensing and regulation of protective T cell immune response during flavivirus infection. West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses that globally cause annual epidemics of virus-induced encephalitis. T here is no approved vaccine or therapy for use in humans to treat WNV infection and the current vaccines to prevent JEV infection do not provide life-long protective immunity. Protection against WNV and JEV is mediated by both innate and adaptive immune responses. The RlG-1 like receptors (RLR) are cytosolic pathogen recognition receptors that recognize non-self RNA and signal through the MAVS adaptor protein to trigger innate antiviral immunity against WNV and JEV. In addition to their role in innate immunity, our laboratory recently discovered that components of the RLR pathway are critical for programming protective adaptive immune responses responsible for clearing virus during the later stages of infection. This includes MAVS-mediated regulation of humoral and cell-mediated immune responses (CD8+, CD4+ and Treg responses) as well as LGP2-mediated regulation of T cell immunity during WNV infection. LGP2 was found to function in a cell-intrinsic manner to control CD8+ T cell survival and effector properties. These findings establish that the RLRs regulate the interface between innate and adaptive immunity during flavivirus infection. However, the immunological mechanism underlying RLR regulation of T cell immunity against flavivirus infection and vaccination are not well understood. Project 4 studies will (1) determine the role of RLR signaling and function in regulating T cell priming; (2) define the Tcell intrinsic function of MAVS and LGP2 in regulating effector and memory T cell responses; (3) determine how MAVS and LGP2 function to regulate memory T cell recall responses. This work will reveal novel insights into innate immune regulation of immunological memory and identify new therapeutic targets and strategies for vaccine protection against flavivirus infection.